1. Field of the Invention
This invention is directed to methods for reducing the degree of inflammation arising from a secondary immune response in a mammal due to antigen exposure (challenge) by the time dependent administration of an oligosaccharide glycoside related to blood group determinants having a type I [.beta.Gal(1.fwdarw.3)GlcNAc] or a type II [.beta.Gal(1.fwdarw.4)GlcNAc] core structure.
The methods of this invention are directed to the discovery that the reduction in antigen induced inflammation in sensitized mammals by administration of oligosaccharide glycosides related to blood group determinants having a type I or a type II core structure is critically dependent on the point in time when that oligosaccharide glycoside is administered.
2. References
The following publications and patent applications are cited in this application as superscript numbers at the relevant portion of the application:
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PA0 72. Petrakova, et al., Can. J. Chemistry, 70: 233-240 (1992). PA0 73. Ichikana, et al., Anal. Biochem., 202: 215-138 (1992) PA0 74. Weinstein, et al., J. Biol. Chem. 257: 13835-13844 (1982). PA0 75. Sticher, et al., Biochem. J., 253: 577-580 (1988). PA0 76. Dean, et al., Chromatogr., 165: 301-319 (1979). PA0 77. Mazid, et al., U.S. Pat. No. 5,059,535, "Process for the Separation and Purification of Sialyl Transferases" issued Oct. 22, 1992. PA0 78. Matsumoto, et al., Anal. Biochem., 116: 103-110 (1981). PA0 79. Schmidt, et al., Liebigs Ann. Chem., 121-124 (1991) PA0 80. Nunez, et al., Can. J. Chem., 59: 2086-2095 (1981) PA0 81. Veeneman, et al., Tetrahedron Lett., 32: 6175-6178 (1991) PA0 82. Hanessian, Carbohydr. Res., 2: 86-88 (1966). PA0 83. Zbiral, et al., Monatsh. Chem., 119: 127-141 (1988). PA0 84. Hasegawa, et al., J. Carbohydr. Chem., 8:135-144 (1989). PA0 85. Kean, et al., J. Biol. Chem., 241: 5643-5650 (1960). PA0 86. Gross, et al., Biochemistry, 28: 7386-7392 (1989). 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All of the above publications and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
The administration to mammals of different oligosaccharide glycosides related to blood group determinants having a type I or type II core structure, such as .alpha.Neu5Ac(2.fwdarw.3).beta.Gal(1-4)-[.alpha.-L-Fuc(1-3)]-.beta.GlcNAc- OR ("Sialyl Lewis.sup.X -OR"), .alpha.Neu5Ac(2.fwdarw.3).beta.Gal(1-3)-[.alpha.-L-Fuc(1-4)]-.beta.GlcNAc- OR (Sialyl Lewis.sup.A -OR), .alpha.Neu5Ac(2.fwdarw.6).beta.Gal-(1-4)-[.alpha.-L-Fuc(1-3)]-.beta.GlcNAc -OR, and the like, has been disclosed by Gaeta, et al..sup.1, Paulson, et al..sup.2,3, Brandley, et al..sup.4, Lowe.sup.5, McEver.sup.6, Furie, et al..sup.7, among others, to reduce inflammation in the mammal arising from a variety of conditions such as injury, infection, exposure to an antigen, etc. These disclosures are based on the fact that an integral step in the inflammatory process in a mammal is the adherence of leukocytes to one or more selectins and the discovery that such oligosaccharide glycosides adhere/bind to one or more selectins involved in the inflammatory response thereby interfering with the binding of the leukocyte to those selectins.
Specifically, the presence of selectins such as ELAM-1 (Endothelium Leucocyte Adhesion Molecule-1) on the vascular endothelium and/or the presence of PADGEM (also referred to as GMP-140) on either the vascular endothelium or on activated platelets and/or the presence of L-selectin on high endothelial venuels (HEV) in the peripheral and mesenteric lymph nodes is believed to be stimulated by an inflammatory event such as exposure to an antigen, myocardial infarction, lung injury, etc. In turn, adhesion of circulating leukocytes (e.g., neutrophils, monocytes, etc.) to ELAM-1 and/or PADGEM located on the stimulated vascular endothelium and/or to PADGEM located on activated platelets are believed to be primary events of the inflammatory response. Additionally, the L-selectin is believed to be present on neutrophils and, accordingly, may play some role in the inflammatory process.
Based on in-vitro data demonstrating that certain oligosaccharide glycosides related to blood group determinants having a type I or type II core structure (e.g., Sialyl Lewis.sup.X and Sialyl Lewis.sup.A) bind to the ELAM-1.sup.1,2,3,4,5,6 selectin and possibly other selectins and that certain oligosaccharide glycosides related to blood group determinants having a type I or type II core structure (e.g., .alpha.Neu5Ac(2.fwdarw.6).beta.Gal(1-4)-[.alpha.-L-Fuc(1-3)]-.beta.GlcNAc) bind to the ELAM-1.sup.4 and PADGEM.sup.7 selectins, it was postulated that these oligosaccharide glycosides would reduce inflammation when administered prophylactically.sup.1,2,3,4 or therapeutically.sup.1,2,3,4,5,6,7 to a mammal by interfering with adhesion between ELAM-1, PADGEM, and/or other selectins and the circulating leukocytes.
In disease/inflammatory conditions, the Gaeta, et al..sup.1, Paulson, et al..sup.2,3 and Brandley, et al..sup.4 references recite that the therapeutic administration of the therein disclosed oligosaccharide glycosides can be conducted on a patient already suffering from the disease/inflammatory condition. According to the Gaeta, et al..sup.1 and Paulson, et al..sup.2,3 references, the therein disclosed oligosaccharide glycosides can be used to treat a variety of disease/inflammatory conditions including disease conditions arising from antigen exposure such as rheumatoid arthritis, asthma, dermatitis, psoriasis, and inflammatory bowel disease as well as inflammatory conditions arising from an injury including frost-bite injury, reperfusion injury, acute leukocyte-mediated lung injury, etc. The Gaeta, et al..sup.1 and Paulson, et al..sup.2,3 references specifically recite that for inflammation arising from reperfusion or other injury, the therein disclosed oligosaccharide glycoside should ideally be administered as soon as possible after the injury. However, no guidance is provided by these or by the Brandley, et al..sup.4, Lowe.sup.5, McEver.sup.6 or Furie, et al..sup.7 references as to when such oligosaccharide glycosides specifically should be therapeutically administered to a mammal sensitized to an antigen after subsequent antigen exposure.
This invention is directed to the discovery that, in order to reduce inflammation in the case of antigen challenge (exposure) in a sensitized mammal, the oligosaccharide glycoside related to blood group determinants must be administered after initiation of the mammal's secondary immune response to the antigen challenge but at or prior to one-half that period of time where the mammal experiences maximal inflammatory response.
Specifically, the data set forth in the examples below evidence that administration of the oligosaccharide glycoside related to a blood group determinant having a type I or type II core structure prior to initiation of the mammal's immune response, provides no reduction in inflammation. Additionally, administration of the oligosaccharide glycoside at a point in time after one-half that period of time where the mammal experiences maximal inflammatory response to the antigen exposure results in minimal reduction in inflammation. In fact, the data evidence that it is only when the oligosaccharide glycoside related to blood group determinants having a type I or type II core structure is administered after the sensitized mammal's secondary immune response has been initiated to antigen challenge but at or prior to about one-half that period of time where the mammal experiences maximal inflammatory response to the antigen challenge does significant reduction in inflammation occur.
These findings are particularly surprising in view of the fact that the Gaeta, et al..sup.1, Paulson, et al..sup.2,3, Brandley, et al..sup.4 references state that the therein disclosed oligosaccharide glycoside can be administered either prophylactically or therapeutically and further in view of the fact that none of the Gaeta, et al..sup.1, Paulson, et al..sup.2,3, Brandley, et al..sup.4, Lowe.sup.5, McEver.sup.6, Furie et al..sup.7 references disclose any criticality with regard to the point in time when such oligosaccharide glycosides should be therapeutically administered to a mammal in order to reduce the degree of inflammation arising from the mammal's secondary immune response to an antigen challenge.